A Novel Dipeptide NGF Mimetic GK-2 Selectively Activating the PI3K/AKT Signaling Pathway Promotes the Survival of Pancreatic β-Cells in a Rat Model of Diabetes

Abstract

We investigated the cytoprotective effect of a novel low-molecular-weight NGF mimetic, GK-2 (hexamethylenediamide bis-N-monosuccinyl-L-glutamyl-L-lysine), on pancreatic β-cells. The neuroprotective effect of GK-2 had been previously shown to be associated with selective activation of the PI3K/Akt signaling pathway. In this study, rats with streptozotocin (STZ)-induced type 2 diabetes mellitus were used. Metformin was used as a reference drug. STZ was immunohistochemically demonstrated to reduce the number of β-cells and affect their morphological structure. Treatment of diabetic animals with GK-2 (at a dose of 0.5 mg/kg intraperitoneally or 5 mg/kg orally) or metformin (300 mg/kg orally) for 28 days reduced the damaging effect of STZ. The effect of GK-2 on manifestations of STZ-induced diabetes, such as hyperglycemia, weight loss, polyphagia, and polydipsia, was comparable to that of metformin, while the cytoprotective activity of GK-2 was slightly stronger than that of metformin. A strong positive correlation between morphometric parameters and the blood glucose level was revealed. The GK-2 cytoprotective effect on β-cells is supposed to manifest through the PI3K/Akt signaling pathway.

Keywords: GK-2; NGF; PI3K/Akt pathway; diabetes; metformin; neurotrophins.

Fig. 1

The influence of GK-2 and metformin on water consumption in Wistar rats. A – GK-2; B – metformin. * – Statistical significance of differences between the experimental group and active control, p < 0.05. ** – Statistical significance of differences between passive control and active control, p < 0.05. # – Statistical significance of differences between experimental groups, p < 0.05

Fig. 2

Pancreatic islets of animals from different groups. Magnification ×620 (upper panel) and ×1,600 (bottom panel). A, A’ – passive control animals; B, B’ – active control animals; C, C’ – diabetic rats treated with intraperitoneal GK-2; D, D’ – diabetic rats treated with oral GK-2; E, E’ – diabetic rats treated with metformin

Fig. 3

Percentage (%) of β-cell islets of different areas (μm2). A – passive control animals; B – active control animals; C – diabetic rats treated with intraperitoneal GK-2; D – diabetic rats treated with oral GK-2; E – diabetic rats treated with metformin

Fig. 4

Correlation between the blood glucose level and the relative β-cell area in pancreatic sections. A – GK-2; B – metformin